Assessing DDIs Through Cyp Inhibition Profile Analysis
The majority of pharmacokinetic drug-drug interactions involving psychotropic medications are due to the cytochrome P450 (CYP) system. Indeed, antipsychotic drugs are mainly metabolised by CYPs, as is the case for the majority of xenobiotics.
Chlorpromazine, fluphenazine, haloperidol, pimozide, risperidone and aripiprazole all strongly inhibit the activity of CYP2D6 (Figure 3) leading to significant drug−drug interaction with CYP 2D6 substrates in humans. Haloperidol, risperidone, chlorpromazine, pimozide and aripiprazole also inhibit the activity of the main CYP3A4 responsible for the metabolism of a number of drugs, which could cause further drug−drug interactions. However, antipsychotics seem not to have any inhibition effect on other CYPs.
All metabolic data for each compound can easily be viewed using the Reaxys Medicinal Chemistry (Figure 4). For each data point, the parameter measured, the value, target, target species, tissue/organ, dose and reference are all shown, and both quantitative and qualitative results are available in the database.
QT Interval Prolongation Through hERG Blockade
Ventricular arrhythmias are the most important cardiac effects of psychotropic drugs and are to a large extent due to prolongation of the QT interval on the electrocardiogram. This phenomenon is determined by several factors, especially blockade of the rapid component of the delayed rectifier potassium current (IKr), encoded by the hERG channel, responsible for repolarization of cardiac cells in the later phase of the cardiac action potential.
Most of antipsychotics inhibit hERG channel activity with a pX > 6 (IC50 < 1 μM), except for thiothixene and fluphenazine (Figure 5). Moreover, chlorpromazine, clozapine, olanzapine, ziprasidone, resperidone and aripiprazole exhibit pX values between 6 and 7 (IC50 = 100 nM – 1 μM). Haloperidol and pimozide are potent inhibitors of the potassium-gated ion channel with pX values of 8 (IC50= 10 nM) and 9 (IC50 = 1 nM), respectively.
Co-prescribing more than one drug that lengthens the QT interval prolongation is potentially dangerous. The same risk exists when a drug that increases the QT interval is co-administered with a compound that inhibits its metabolism leading to a significant increase in systemic blood concentration and consequently an increased risk of QT prolongation. Antipsychotics known to block the hERG channel, to lengthen the QT interval, and to inhibit CYPs are generally co-prescribed in clinical practice, and little research has been conducted into polypharmacy efficacy or adverse effects (5)Ganguly, R. Kotzan, J.A., Miller, L.S., Kennedy, W.K. and Martin B.C. (2004)
Prevalence, trends, and factors associated with antipsychotic polypharmacy among medicaid-eligible schizophrenia patients, 1998–2000. J Clin Psychiatry 65: 1377–1388. . Hence, knowledge generated regarding metabolism and hERG activity may be helpful to avoid possible unsafe combinations with antipsychotics.
In the process of drug development, new compounds having a specific profile of selectivity toward antipsychotic action have to be compared to already describe drugs to assess their activity and safety.
The first step to compare new molecule profiles to existing antipsychotics is to collect all accessible information mainly in published scientific literature (articles, patents, FDA regulatory reviews). Since 1952 and the first use of chlorpromazine in clinic, a large amount of data are available to report the effects (and adverse effects) of antipsychotic drugs and to determine their mechanisms of action. This represents a vast amount of knowledge and the full analysis of this information is time consuming. Reaxys Medicinal Chemistry allows researchers to gain time in this analysis and provide data for understanding toxicity properties of antipsychotics. In addition, using Reaxys Medicinal Chemistry allows R&D scientists to generate original profiles with safety optimization of new candidates.
Essential Drug Discovery Solution
Reaxys Medicinal Chemistry is an extensive database containing chemical information linked to in vitro and in vivo biological activities extracted from over 300,000 articles, 90,000 patents and 5,000 journals. More than 6 million chemical compounds are associated with their biological data (> 29 million bioactivity data points) and linked to information on 12,700 pharmacological targets, allowing the scientists to reveal connections between compounds, effects and targets. The data is indexed and normalized for maximum searchability and consistency.
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- Ganguly, R. Kotzan, J.A., Miller, L.S., Kennedy, W.K. and Martin B.C. (2004)
Prevalence, trends, and factors associated with antipsychotic polypharmacy among medicaid-eligible schizophrenia patients, 1998–2000. J Clin Psychiatry 65: 1377–1388.